Our long-term goal is to develop biodegradable synthetic hydrogels for regenerating articular cartilage, which are capable of supporting the normal forces in vivo while simultaneously permitting matrix deposition and new tissue growth. Current limitations in the development of such hydrogels can be summarized as follows: (a) highly cross-linked hydrogel can resist loads but restrict matrix diffusion, which prevents growth of new tissue (b) reversely, low cross-link density permits matrix diffusion but results in unacceptably weak bulk properties that cannot sustain normal forces. The objective of this work is thus to introduce a hydrogel system for which spatial and temporal degradation can be controlled to better match tissue development. Our global hypothesis is that a bimodal degrading hydrogels, incorporating localized and cell-mediated (enzymatic) and bulk (hydrolytic) degradation, maintains mechanical integrity while simultaneously allowing matrix development and that there exists an optimized design space to achieve the outcomes. To test our hypothesis, mathematical models will be developed in tandem with experiments in order to accurately describe the combined effects of gel degradation and matrix deposition. In particular, the specific aims of the project are to: 1. Develop, validate, and calibrate a mathematical model for bimodal degrading hydrogels. This aim will be decomposed in two parts. First, our existing model for matrix degradation will be validated against experimental measurement based on enzyme-loaded microparticles. Second, a model for ECM production and deposition, combined with hydrolytic degradation will be developed and validated against preliminary data. 2. Characterize degradation behavior and matrix evolution in single and dual mode degrading hydrogel. This aim will extend the mathematical model to the general case of a combination of bimodal degradation and ECM deposition in order to assess the effect of hydrogel parameters on the competition between gel degradation and ECM deposition. Two experimental strategies, testing both enzymatic and bimodal degradable gels, are then proposed to validate and calibrate the model. At the completion of this exploratory research, we expect to have developed a new class of bimodal degrading hydrogels based on crosslinked poly(ethyelene glycol) where the crosslinks can be degraded either through cell-mediated enzymatic degradation (i.e., aggrecanses secreted by entrapped chondrocytes) or hydrolytically (i.e., poly(lactic acid) segments). By merging experiments with modeling, we expect to clearly understand how a bimodal degradable gel can be used to maintain mechanical integrity while permitting macroscopic tissue evolution. In future work, this model system will enable us to develop superior degradable hydrogels, which will lay the foundation for seeking competitively a NIH R01 and to pursue their (pre)clinical utility. PUBLIC HEALTH RELEVANCE: This research aims to create a new class of biodegradable scaffolds that are in tune with new tissue development for treating damaged cartilage. New mathematical tools will be developed to elucidate scaffold design parameters that yield superior engineered tissues.